The present invention relates to processes for producing aspartyl dipeptide ester derivatives, such as N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester, which are important sweeteners with a high degree of sweetness. This process may include processes for crystallization and employ novel aldehyde derivatives as intermediates.
In recent years, as eating habits have increased, excessive weight gain and obesity caused by excessive sugar intake has been more frequently observed. Additionally, diseases accompanied by such weight gain and obesity are becoming more prevalent. Accordingly, the development of a low-calorie sweetener (sweetening agent) that replaces sugar has been strongly in demand. Aspartame is widely used as a sugar substitute or sweetener; and is excellent in safety and sweetening quality. However, a drawback of aspartame is that is somewhat unstable.
The present inventors have found that N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester, shown in the following formula, is useful as a sweetener and is excellent in stability. Furthermore, this ester compound has a degree of sweetness and therefore, has the advantage in cost. 
Because sweeteners are primarily used in foods and pharmaceuticals, which are to be consumed by a person, the sweeteners should be purified to high purity, that is essentially free of impurity and/or decomposed materials. Furthermore, where peptide-based sweeteners are employed, which may decompose rather easily, there exists a need to provide such sweeteners in a stable form, to prevent decomposition during storage and shipment.
In a process for producing N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester a xcex2-O-benzyl-xcex1-L-aspartyl-L-phenylalanine methyl ester is reductively alkylated with 3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutylaldehyde and NaB(OAc)3H, which is followed by removing the benzyl moiety of a protecting group. However, 3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutylaldehyde is prepared by a 7 step process starting from 3-hydroxy-4-methoxyacetophenone, as shown in the following reaction process 1, and therefore the compound is not well suited to be used to provide a industrially profitable process. 
Therefore, a problem to be solved by the present invention is to provide an efficient process for producing N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester. The invention also provides a practical and industrial process for purifying this ester compound and in particular for obtaining the ester compound in the crystalline form at a high purity.
The present inventors have found that an aspartyl dipeptide ester derivative represented by formula (2) can be obtained in a process by reductively alkylating aspartame with an aldehyde represented by formula (1), preferably in the presence of catalyst, more preferably in the presence of hydrogen. 
where in formulas (1) and (2), R1, R2, R3, R4 and R5 are independently a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, a benzyloxy group and a hydroxyalkyloxy group having 2 or 3 carbon atoms, wherein two symbols of R1 and R2, or two symbols of R2 and R3 may form a methylene dioxy group, and
provided that in the formula (2), any one of R1, R2, R3, R4 and R5 is not a benzyloxy group.
The inventors have also succeeded in synthesizing a novel 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutylaldehyde, which can be used as an intermediate in the above production process
In one embodiment of the invention, the process comprises the steps outlined in the reaction process 2 depicted below. 
Another object of the present invention is 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutylaldehyde, which can be employed as an intermediate for producing N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester and which is advantageous compared to a process for producing 3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutylaldehyde described above.
The 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutylaldehyde can be synthesized, for example, in a process where 2-halogenoanisole is reacted with 3-methylcrotonic acid, preferably in the presence of an acid. This reaction is followed by a conversion of a halogen atom in the 3-(3-halogeno-4-methoxyphenyl)-3-methylbutyric acid obtained into a hydroxyl group by alkaline hydrolysis, in the presence of a copper catalyst. The carboxylic acid is then converted to an aldehyde.
Another object of the invention is a process for producing N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester at a high purity, which involves crystallization.